Transcript APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE

APPROVED DRUG PRODUCTS
WITH THERAPEUTIC
EQUIVALENCE EVALUATIONS
( THE ORANGE BOOK )
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Health Care Costs Continue to Increase upto 44% by 2006
So health cost of patient increases since branded drugs are costly
Clinicians are increasingly encouraged to prescribe GENERIC drugs for effective treatment
Before substituting a generic product, physicians and other decisions makers should consider the potential clinical and
pharmacoeconomic consequences like Over and Undertreatment, Adverse effects, Additional expenses and Cost savings
To help avoid complications arising from product substitution, the FDA established a list of generic drugs that can be safely and
appropriately substituted for brand products
The FDA has prepared a list of drugs that are bioequivalent they can be substituted for each other
These drugs are listed in a federal publication called Approved Drug Products With Therapeutic Equivalence Evaluations
known as the Orange Book
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CONTENT . . .
A.
WHAT IS THE NEED OF “ THE ORANGE BOOK ” ?
B.
INTRODUCTION TO “ THE ORANGE BOOK ” ?
1.
2.
3.
Definition
History
Objectives
C.
CONTENTS OF “ THE ORANGE BOOK ”
D.
CUMMULATIVE SUPPLEMENT
E.
WHAT IS “ THE GREEN BOOK ” AND “ THE BLUE BOOK ” ?
F.
QUESTIONS
G.
REFERENCES
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B. INTRODUCTION TO “
THE ORANGE BOOK ” ?
1.
2.
3.
Definition
History
Objectives
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1. Definition
 It is the publication of “Approved Drug Products With Therapeutic Equivalence
Evaluations” by the Food and Drug Administration.
 It is prepared by The Orange Book Staff, Center for Drug Evaluation and Research.
 It identified drug products on the basis of safety and effectiveness by the Food and Drug
Administration under the Federal Food, Drug, and Cosmetics Act.
 Drugs marketed only on the basis of safety or pre-1938 drugs.
 The list is independent of any current regulatory action against a drug product.
 The main criterion for the inclusion of any product is that the product is the subject of an
application with an effective approval that has not been withdrawn for safety or efficacy
reasons.
 The FDA does not recommend substituting drugs that have not been determined to be
bioequivalent.
 Drugs that are not listed as bioequivalent should not be substituted for each other.
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2. History
YEAR
ACTION
May 31, 1978
The Commissioner of the Food and Drug Administration sent a letter to officials of
each state stating FDA's intent to provide a list of all prescription drug products
that are approved by FDA for safety and effectiveness, along with therapeutic
equivalence determinations for multisource prescription products.
January, 1979
The list was distributed (included only currently marketed prescription drug
products approved by FDA through NDAs and ANDAs under the provisions of
section 505 of the Act)
October 31, 1980
The final rule (includes FDA’s response to the public comments on the proposal)
was published in the Federal Register (45 FR 72582).
The list incorporated appropriate corrections and additions.
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3. Objectives
To allow
review of
patterns of
access
and usage
To allow
discovery of
use of
unusual
privileges
To allow
discovery of
repeated
attempts
to bypass
protections
To serve
as a
deterrent
by its
existence
To supply
an
additional
form of user
assurance
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C. CONTENTS OF “ THE
ORANGE BOOK
(PREFACE TO 27 EDITION)
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1.
INTRODUCTION
1.1
Content and Exclusion
1.2
Therapeutic Equivalence-Related Terms
1.3
Statistical Criteria for Bioequivalence
1.4
Reference Listed Drug
1.5
General Policies and Legal Status
1.6
Practitioner/User Responsibilities
1.7
Therapeutic Equivalence Evaluations Codes
1.8
Description of Special Situations
1.9
Therapeutic Equivalence Code Change for a Drug Entity
1.10
Change of the Therapeutic Equivalence Evaluation for a Single Product
1.11
Discontinued Section
1.12
Changes to the Orange Book
1.13
Availability of the Edition
2.
HOW TO USE THE DRUG PRODUCTS LISTS
2.1
Key Sections for Using the Drug Product Lists
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2.2
Drug Product Illustration
2.3
Therapeutic Equivalence Evaluations Illustration
DRUG PRODUCT LISTS
Prescription Drug Product List
OTC Drug Product List
Drug Products with Approval under Section 505 of the Act Administered by the Center for Biologics
Evaluation and Research List
Discontinued Drug Product List
Orphan Products Designations and Approvals List
Drug Products Which Must Demonstrate in vivo Bioavailability Only if Product Fails to Achieve
Adequate Dissolution
APPENDICES
A.
Product Name Index A-1
B.
Product Name Index Listed by
C.
Uniform Terms
PATENT AND EXCLUSIVITY INFORMATION ADDENDUM
A.
Patent and Exclusivity Lists
B.
Patent and Exclusivity Terms
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CONTENTS OF “ THE
ORANGE BOOK
1. INTRODUCTION
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1.1 Content and Exclusion
Approved OTC drug
products for those which are not marketed
Approved prescription drug with
therapeutic equivalence evaluations
Drug products with
Biologics Evaluation and Research
List of approved products
that have been discontinued from marketing
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Cont…
The List also includes:
 Indices of prescription and OTC drug by trade or
established name (if no trade name exists) and by applicant
name (holder of the approved application).
 The list includes applicants’ names in abbreviated form.
 An Addendum contains drug patent and exclusivity
information for the Prescription.
 It includes only full approval products and not tentative
approval products.
The List excludes:
 Distributors or re-packagers of products
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1.2 Therapeutic Equivalence-Related
Terms
Pharmaceutical
equivalents
Pharmaceutical
alternatives
Therapeutic
equivalents
Bioequivalence
Bioavailability
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Pharmaceutical Equivalents
1. Contain the same active ingredient(s),
2. Have the same dosage form and route of
administration, and
3. Identical in strength or concentration
4. May differ in shape, release mechanisms, and
packaging
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Pharmaceutical Alternatives
 Contain the same therapeutic moiety but might
differ in ,
1. Salts, esters, or complexes form of the same
moiety,
2. Different dosage forms,
3. Different strengths
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Therapeutic Equivalents

Therapeutic equivalents are expected to have the same clinical effect
and safety profile.

Drug products are considered therapeutic equivalents if they are all
of the following
1.
Pharmaceutical equivalents
2.
Bioequivalent
3.
Approved as safe and effective
4.
Adequately labeled
5.
Manufactured in compliance with current Good Manufacturing
Practice regulations
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Bioequivalence
 Drug products are considered
bioequivalent if they are
pharmaceutical equivalents
whose rate and extent of
absorption are not statistically
different when administered to
subjects at the same molar dose
under similar experimental
conditions
 Bioequivalence use to
in vitro
test methods
comparative
clinical trials
Demonstrated by
in vivo
test methods
pharmacodynamic
studies
determine Therapeutic
Equivalents
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1.3 Statistical Criteria for
Bioequivalence
 In short Bioequivalence refers to equivalent release of the
same drug substance from two or more drug products.
 The standard bioequivalence (PK) study is conducted in
24-36 adults using a two-treatment crossover study design.
 Alternately, a four-period, replicate design crossover
study can also be used.
 The statistical methodology for analyzing these
bioequivalence studies is called the two one-sided test
procedure.
 Two situations are tested with this statistical methodology.
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Cont…

Pharmacokinetic parameters determine are AUC and Cmax.

1.
Two criteria includes,
Whether a generic product (test), when substituted for a brand-name
product (reference) is significantly less bioavailable. (A limit of test-product
average/reference-product average of 80%)
2.
Whether a brand-name product when substituted for a generic product is
significantly less bioavailable. (A limit of reference-product average/testproduct average 125%)

A difference of greater than 20% for each of the above tests was determined
to be significant

The confidence interval for both pharmacokinetic parameters, AUC and
Cmax, must be entirely within the 80% to 125% boundaries cited above
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Example,
 Product A is bioequivalent to
Pharmacokinetic
Reference Range
125%
100%
80
%
the reference drug; its
confidence interval of the AUC
falls within 80% to 125% of the
reference drug
 Product B is not bioequivalent
to the reference drug; its
confidence interval of the AUC
falls outside of 80% to 125% of
the reference drug
Product A
Reference
Product B
Bioequivalent
Drug
Not Bioequivalent
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1.4 Reference Listed Drug
 A reference listed drug means the listed drug identified by FDA as the
drug product upon which an applicant relies in seeking approval of its
ANDA.
Bioequivalence study carried out
Applicant's product
Compared with reference standard
In vivo & Invitro
 The aim of FDA is to avoid possible significant variations among
generic drugs and their brand name counterpart.
 The reference listed drug is identified by the symbol "+" in the
Prescription and Over-the-Counter (OTC) Drug Product Lists.
 List is available for oral dosage forms, injectables, ophthalmics, otics,
and topical products.
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1.5 General Policies and Legal Status
 The List contains public information and advice.
 It is not compulsory the drug products which may be
purchased, prescribed, dispensed, or substituted for one
another, nor does it, should be avoided.
 Exclusion of a drug product from the List does not
necessarily mean that the drug product is not safe or
effective, or that such a product is not therapeutically
equivalent to other drug products.
 Rather, FDA has not evaluated the safety, effectiveness,
and quality of the drug product.
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1.6 Practitioner/User Responsibilities

Professional care and judgment should be exercised in using the list.

Practitioner should be aware of the multi-source and single-source drug
products.
Multisource Drug Product means those pharmaceutical equivalents
available from more than one manufacturer. For such products, a therapeutic
equivalence (TE) code is included and, in addition, product information is
highlighted in bold face and underlined.
Single-Source Drug Product means only one approved product is available
for particular active ingredient, dosage form, route of administration, and
strength. For such product no therapeutic equivalence code is included.
1.
2.

Products on the List are identified by the names of the holders of approved
applications (applicants) who may not necessarily be the manufacturer of the
product:

Applicants like Manufacture, Contract Manufacturer, Repackager,
Distributor or Marketer.
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1.7 Therapeutic Equivalence
Evaluations Codes
The coding system for therapeutic equivalence evaluations
First letter : therapeutically equivalent to other pharmaceutically equivalent products
Second letter : provide additional information on the basis of FDA's evaluations

A CODES

B CODES
1.
TE rating is assigned to PE products as they
are manufactured in accordance with cGMP
regulations and meet the other requirements
of their approved applications or
1.
Documented
bioequivalence problems
and no adequate
bioequivalence have been
submitted to FDA
2.
For those DESI (Drug Efficacy Study
Implementation) drug products and for post1962 drug products in a dosage form
presenting a potential bioequivalence
problem, an evaluation of TE is assigned to
PE, if approved application contains
scientific evidence establishing through in
vivo and in vitro studies.
2.
The quality standards are
inadequate to determine
therapeutic equivalence
3.
The drug products are
under regulatory review
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Code ‘A’: Drug product that FDA
considers to be therapeutically equivalent
Sr.
Codes
Description
1.
AA
Products in conventional dosage forms not presenting bio-equivalence
problems (All oral dosage forms)
2.
AB
Products meeting necessary bio-equivalence requirements
(AB1,
AB2,
AB3 …)
product )
(In certain instances, a number is added to end of the AB code to make a three character code, which is
assigned only in situations when more than one reference listed drug of the same strength has been
designated under the same heading.
Two or more reference listed drugs are generally selected only when there are at-least two potential
reference drug products which are not bio-equivalent to each other)
AN
Solutions and powder for aerosolization (Marketed for use in any of several delivery
3.
(Multisource drug
systems)
4.
AO
Injectable oil solutions
5.
AP
Injectable aqueous solutions and in certain cases, intra-venous non-aqueous
solutions (Different routes of administration, Different preservatives or no preservatives, Dry
powders for reconstitution, Concentrated sterile solutions for dilutions, Sterile solutions ready for
injection Should produce same concentration prior to injection)
6.
AT
Topical products
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Code ‘B’: Drug product that are not to
be therapeutically equivalent
Sr
Codes
Description
1.
B*
Drug products requiring further FDA investigation and review to determine therapeutic
equivalence.
2.
BC
Extended release dosage forms (capsules, injectable and tablets bioequivalence data have not been
submitted).
3.
BD
Active ingredients and dosage forms with documented bio-equivalence problems (Adequate
studies have not been submitted to FDA since due to bio-equivalence problems).
4.
BE
Delayed release oral dosage forms (Significant differences in absorption).
5.
BN
Products in aerosol-nebulizer drug delivery systems (differences in the dose of drug and particle
size delivered by different products)
6.
BP
Active ingredients and dosage forms with potential bio-equivalence problems
7.
BR
Suppositories or enemas that delivers drug for systemic absorption
8.
BS
Products having drug standard deficiencies (variation in pharmacologically active components)
9.
BT
Topical product for which the data are in-sufficient to determine therapeutic equivalence
10
BX
Drug products for which the data are insufficient to determine therapeutic equivalence
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1.8 Description of Special Situations
Drugs
Description of Special Situations
Amino-acid and Protein
Hydrolysate injections
These products differ in the amount and kinds of amino-acids they
contain, and therefore, are not considered pharmaceutical equivalents.
For this reasons, these products are not considered therapeutically
equivalent.
Follitropin alpha and beta
Physico-chemical tests and bio-assay, follitropin alpha and follitropin
beta are indistinguishable
Gaviscon® tablets
Gaviscon® is an OTC product which has been marketed since
September 1970. The active ingredients in this product, aluminum
hydroxide and magnesium trisilicate, were reviewed by the Agency's
OTC Antacid Panel . However, the tablet failed to pass the antacid test
which is required of all antacid products. The Agency, therefore, placed
the tablet in Category III for lack of effectiveness.
Patent certification (s)
Reference listed drug based
upon a suitability petition
ANDA that refers to a Reference Listed Drug (RLD) approved pursuant
to a suitability petition must demonstrate that the proposed product is
bioequivalent to the RLD
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1.9 Therapeutic Equivalence Code
Change for a Drug Entity
 Such change occur in response to a petition or on its own
initiative.
 Changes will generally occur when new scientific
information affects the therapeutic equivalence of an entire
category of drug products in the List.
 The change may be from the code,
AA
No Bioequivalence problem
BP
Bioequivalence problem
 This procedure does not apply to a change of a particular
product code (e.g., a change from BP to AB or from AB to
BX).
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1.11 Discontinued Section
1.
When the product have been discontinued from
marketing,
2.
Are for military use,
3.
Or have had their approvals withdrawn for other than
safety or efficacy reasons
4.
Drug Products for exportation
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CONTENTS OF “ THE
ORANGE BOOK
2. HOW TO USE THE DRUG PRODUCT
LISTS
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2.1 Key Sections for Using the Drug
Product Lists.

1.
2.
3.
4.
5.
This contains illustrations, along with Drug Product Lists, indices,
and lists of abbreviations and terms which facilitate their use.
Illustration: Depicts the format found in the Prescription Drug
Product List.
Drug Product Lists: The Prescription and OTC drug product lists,
arranged alphabetically by active ingredient (s), contains product
identification information (active ingredients, dosage forms, routes
of administration, product names, application holders, strengths) for
single and multiple ingredient drug products. Also shown are the
application number and drug product number.
Product Name Index.
Product Name Index Listed by Applicant.
Uniform terms.
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2.2 Drug Product Illustration
SINGLE INGREDIENT
ACTIVE INGREDIENT
DOSAGE FORM : ROUTE OF ADMINISTRATION
MEPIRIDINE HYDROCHLORIDE
INJECTABLE : INJECTION
TRADE OR GENERIC NAME
HEXANON
REFERENCE LISTED DRUG
AP + METRO – PHYS
AP +
AP +
AP +
MEPIRIDINE HCL
TE CODE FOR MULTISOURCE PRODUCT
FINAL APPROVAL DATE
SINGLE SOURCE PRODUCT (NO TE CODE)
AP DONHARE PHARM
AP
AP
25 mg / ml
50 mg / ml
75 mg / ml
100 mg /
ml
25 mg / ml
50 mg / ml
75 mg / ml
AP
AP
100 mg / ml
JOHONSON MED
AP HOLOVAC LLC
OBS PHARM
10 mg / ml
25 mg / ml
150 mg / ml
N13111 001
N13111 002
N13111 003
Aug 22, 1983
N13111 004
Jan 19, 1985
N11586 001
N12569 001
N14458 002
Aug 11, 1987
N22543 004
Aug 28, 1987
N11786 002
N24765 003
N03841 003
APPLICANT
AVAILABLE STRENGTH OF PRODUCT
APPLICANT NUMBER & PRODUCT NUMBER
PRODUCT NUMBER IS FOR FDA INTERNAL COMPUTER DATA USE ONLY
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Example
ALBUTEROL : AEROSOL, METERED; INHALATION
VENTOLIN : AB + GLAXOSMITHKLINE 0.09MG/INH N18473 001
ALBUTEROL : AB ARMSTRONG PHARMS 0.09MG/INH N72273 001 Aug 14, 1996
AB GENPHARM
0.09MG/INH N73045 001 Aug 19, 1997
Albuterol :
Active Ingredient
Aerosol, Metered; Inhalation : Dosage Form / Route of Administration
Ventolin :
Proprietary Name
Albuterol :
Generic Name
GlaxoSmithKline, :
Manufacturer
‘+’ sign :
Indicates Ventolin is Reference Listed Drug (RLD)
AB :
Therapeutic Equivalence (TE) Code
Amstrong Pharm, Genpharm : Applicant
0.09MG/INH :
Strength
N18473 001, N72273 001, : Application Number and Product Number of respective
products
Aug 14 1996, Aug 19 1997: Final Approval Date
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2.3 Therapeutic Equivalence
Evaluations Illustration
SULFASALAZINE
TABLET : ORAL
FAZINE
AB
Product consider therapeutically equivalent to each other
PARKLAND
500 mg
N4 2999 001
500 mg
N4 0222 001
500 mg
N4 1297 001
SULAZINE
AB
URSA
SULFASALAZINE
Product consider not therapeutically equivalent to any other
product listed
BP
BROWN
SULFASALAZINE
TABLET : ORAL
FAZINE
AB
Product consider not therapeutically equivalent to each
other
PARKLAND
500 mg
N4 2999 001
SULFASALAZINE
BP
BROWN
500 mg
N4 1297 001
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Cont…
 Drug Product reviewed through DESI are not included
 It includes only full approval products and not tentative approval
products
 Drug Product of Repackager/Distributor is considered to be
therapeutically equivalent to the Application Holder’s product
 Even if the Application holder’s drug product is single source or
coded as nonequivalent, repackager’s or distributor’s product is
TE to Application Holder’s product
 The new approvals and required changes in data are included in
each subsequent edition. Even monthly cummulative supplements
are published
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DRUG PRODUCT LISTS
1.
Prescription Drug Product List
2.
OTC Drug Product List
3.
Drug Products with Approval under Section 505 of the Act
Administered by the Center for Biologics Evaluation and Research
List
4.
Discontinued Drug Product List
5.
Orphan Products Designations and Approvals List
6.
Drug Products Which Must Demonstrate in vivo Bioavailability
Only if Product Fails to Achieve Adequate Dissolution
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APPENDIX
A. Appendix A: Product Name Index, is an index of
Prescription and OTC Drug Products by established or
trade names.
B.
Appendix B: Product Name Index Listed by Applicant, is
an index of Prescription and OTC Drug Products that
cross references applicants to drug products.
C.
Appendix C: Uniform terms, To improve readability,
uniform terms are used to designate dosage forms, routes
of administration and abbreviations used to express
strengths.
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F. CUMMULATIVE SUPPLEMENT

It is one of a series of monthly updates to the Approved Drug Products with Therapeutic Equivalence
Evaluations.

Provides information on :
Newly approved drugs
Revised therapeutic equivalence evaluations
Updated patent and exclusivity data
Applicant Name Changes

Products that have
Never been marketed,
Are for exportation, or for military use,
Have been discontinued from marketing
That have had their approvals withdrawn for other than safety or efficacy reasons will be
flagged in this. Cumulative Supplement with the "@" symbol to designate their non-marketed status.
(will be included in Discontinued Section)

New additions to the Prescription Drug Product List and OTC Drug Product List are indicated by the
symbol >A>.

The Patent and Exclusivity List new additions are indicated by the symbol >A>

New deletions to the Prescription Drug Product List and OTC Drug Product List are indicated by the
symbol >D> (DELETE)
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G. THE GREEN BOOK & THE
BLUE BOOK
THE GREEN BOOK
 It is a list of all animal drug products
approved for safety and effectiveness.
 It consist of eight sections which are as
follow,
THE BLUE BOOK
 The FDA publication Requirement
of Laws and Regulations Enforced
by the U.S. Food and Drug
Administration
 It has been discontinued as of
October 2002.
Section 1 - NADA Number, Trade Names and
Sponsors arranged by Tradename,
NADA Number
Section 2 - Active Ingredients
Section 3 - Patent Information
Section 4 - Exclusivity Periods
Section 5 - Products Subject to Notice of Hearing
 In its place there is a Wealth Of
Compliance Information on the
FDA Website. For links to this
information, please go to the
Website’s
Industry
Portal<http://www.fda.gov/oc/indu
stry/default.htm>.
Section 6 - Voluntary Withdrawals
Section 7 - Suitability Petition Actions
Section 8 - 2006 Monthly Updates
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H. QUESTIONS

1.
September 2005
Define: Pharmaceutical Equivalents, Pharmaceutical
Alternatives and Therapeutic equivalents. What are the
criteria for these equivalents? (Internals July 2006)
2.
What are the statistical criteria for Bio-equivalence

September 2006
What are Orange Book, Green Book and Blue Book?
Discuss the coding system for Therapeutic Equivalence
Evaluation and how it can be changed giving suitable
illustration? (Internals July 2006)
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I. REFERENCE
 http://www.fda.gov/cder/orange/obannual.pdf
 http://www.fda.gov/cder/orange/obcs.pdf
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THANK YOU
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